The ultimate goal of the proposed research program is the development of both safer and more effective combination chemotherapy for cancer based on biochemical modulation. Drug combinations, or drug-metabolite combinations, selected on the basis of known or potential biochemical interaction will be utilized to manipulate relevant biochemical pathways in a therapeutically beneficial manner to either potentiate selective cytotoxicity in tumor cells, and/or to selectively diminish toxicity in normal host cells. In addition, a monoclonal antibody (MCA) to the epidermal growth factor receptor of the murine breast tumor, will be integrated into a combined treatment plan with the biochemically selected antimetabolite-metabolite combinations. The goal is to increase both the power and selectively of the therapeutic attack, hopefully to the level of cure of advanced, spontaneous solid cancers, first in a murine model and then ultimately in patients. This approach requires the integration of 4 projects: Project 1, Experimental Chemotherapy; Project 2, Biochemical Studies; Project 3, Monoclonal Antibody Studies; and Project 4, Clinical Studies. Preclinical chemotherapy studies (Project 1) will be performed entirely in in vivo murine tumor models. Therapeutic results from a particular drug manipulation, obtained as expected on the basis of the biochemical information that prompted that minipulation, will be confirmed on a biochemical level (Project 2) to insure that the biological results are related to the predicted biochemical changes. Unexpected therapeutic results will be explored at the biochemical level to provide new information that will be utilized to alter the drug combination (or schedule) so as to achieve the desired therapeutic advance. In vivo biochemical and pharmacological studies (Project 2) in the same animal tumor models will provide guidelines for comparative pharmacologic and biochemical studies in the clinic (project 4) which will be used to adjust promising therapeutic drug regimens for translation from the animal tumor model to cancer patients. The combined in vivo biological and biochemical findings, Projects 1, 2, lead to guidelines for specific clinical trails, and feedback from the clinical studies may suggest new experimental studies and refinements.